CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Eun-Young Kang; Ashley Weir; Nicola S Meagher; Kyo Farrington; Gregg S Nelson; Prafull Ghatage; Cheng-Han Lee; Marjorie J Riggan; Adelyn Bolithon; Gordana Popovic; Betty Leung; Katrina Tang; Neil Lambie; Joshua Millstein; Jennifer Alsop; Michael S Anglesio; Beyhan Ataseven; Ellen Barlow; Matthias W Beckmann; Jessica Berger; Christiani Bisinotto; Hans Bösmüller; Jessica Boros; Alison H Brand; Angela Brooks-Wilson; Sara Y Brucker; Michael E Carney; Yovanni Casablanca; Alicia Cazorla-Jiménez; Paul A Cohen; Thomas P Conrads; Linda S Cook; Penny Coulson; Madeleine Courtney-Brooks; Daniel W Cramer; Philip Crowe; Julie M Cunningham; Cezary Cybulski; Kathleen M Darcy; Mona A El-Bahrawy; Esther Elishaev; Ramona Erber; Rhonda Farrell; Sian Fereday; Anna Fischer; María J García; Roy F P M Kruitwagen; Lilian van-Wagensveld; AOCS Group; Susan J. Ramus

doi:10.1002/cncr.34582

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Eun-Young Kang, Ashley Weir, Nicola S Meagher, Kyo Farrington, Gregg S Nelson, Prafull Ghatage, Cheng-Han Lee, Marjorie J Riggan, Adelyn Bolithon, Gordana Popovic, Betty Leung, Katrina Tang, Neil Lambie, Joshua Millstein, Jennifer Alsop, Michael S Anglesio, Beyhan Ataseven, Ellen Barlow, Matthias W Beckmann, Jessica BergerChristiani Bisinotto, Hans Bösmüller, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Sara Y Brucker, Michael E Carney, Yovanni Casablanca, Alicia Cazorla-Jiménez, Paul A Cohen, Thomas P Conrads, Linda S Cook, Penny Coulson, Madeleine Courtney-Brooks, Daniel W Cramer, Philip Crowe, Julie M Cunningham, Cezary Cybulski, Kathleen M Darcy, Mona A El-Bahrawy, Esther Elishaev, Ramona Erber, Rhonda Farrell, Sian Fereday, Anna Fischer, María J García, Roy F P M Kruitwagen, Lilian van-Wagensveld, AOCS Group, Susan J. Ramus^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.

METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.

RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.

CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Original language	English
Pages (from-to)	697-713
Number of pages	17
Journal	Cancer
Volume	129
Issue number	5
Early online date	26 Dec 2022
DOIs	https://doi.org/10.1002/cncr.34582
Publication status	Published - 1 Mar 2023

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Kang, E.-Y., Weir, A., Meagher, N. S., Farrington, K., Nelson, G. S., Ghatage, P., Lee, C.-H., Riggan, M. J., Bolithon, A., Popovic, G., Leung, B., Tang, K., Lambie, N., Millstein, J., Alsop, J., Anglesio, M. S., Ataseven, B., Barlow, E., Beckmann, M. W., ... Ramus, S. J. (2023). CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study. Cancer, 129(5), 697-713. https://doi.org/10.1002/cncr.34582

@article{c478396c2f3041bf8d8ee8eb052ddffb,

title = "CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study",

abstract = "BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.",

author = "Eun-Young Kang and Ashley Weir and Meagher, {Nicola S} and Kyo Farrington and Nelson, {Gregg S} and Prafull Ghatage and Cheng-Han Lee and Riggan, {Marjorie J} and Adelyn Bolithon and Gordana Popovic and Betty Leung and Katrina Tang and Neil Lambie and Joshua Millstein and Jennifer Alsop and Anglesio, {Michael S} and Beyhan Ataseven and Ellen Barlow and Beckmann, {Matthias W} and Jessica Berger and Christiani Bisinotto and Hans B{\"o}sm{\"u}ller and Jessica Boros and Brand, {Alison H} and Angela Brooks-Wilson and Brucker, {Sara Y} and Carney, {Michael E} and Yovanni Casablanca and Alicia Cazorla-Jim{\'e}nez and Cohen, {Paul A} and Conrads, {Thomas P} and Cook, {Linda S} and Penny Coulson and Madeleine Courtney-Brooks and Cramer, {Daniel W} and Philip Crowe and Cunningham, {Julie M} and Cezary Cybulski and Darcy, {Kathleen M} and El-Bahrawy, {Mona A} and Esther Elishaev and Ramona Erber and Rhonda Farrell and Sian Fereday and Anna Fischer and Garc{\'i}a, {Mar{\'i}a J} and Kruitwagen, {Roy F P M} and Lilian van-Wagensveld and {AOCS Group} and Ramus, {Susan J.}",

note = "{\textcopyright} 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.",

year = "2023",

month = mar,

day = "1",

doi = "10.1002/cncr.34582",

language = "English",

volume = "129",

pages = "697--713",

journal = "Cancer",

issn = "0008-543X",

publisher = "John Wiley & Sons Inc.",

number = "5",

}

Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Bösmüller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jiménez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, García, MJ, Kruitwagen, RFPM , van-Wagensveld, L, AOCS Group & Ramus, SJ 2023, 'CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study', Cancer, vol. 129, no. 5, pp. 697-713. https://doi.org/10.1002/cncr.34582

TY - JOUR

T1 - CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma

T2 - An Ovarian Tumor Tissue Analysis consortium study

AU - Kang, Eun-Young

AU - Weir, Ashley

AU - Meagher, Nicola S

AU - Farrington, Kyo

AU - Nelson, Gregg S

AU - Ghatage, Prafull

AU - Lee, Cheng-Han

AU - Riggan, Marjorie J

AU - Bolithon, Adelyn

AU - Popovic, Gordana

AU - Leung, Betty

AU - Tang, Katrina

AU - Lambie, Neil

AU - Millstein, Joshua

AU - Alsop, Jennifer

AU - Anglesio, Michael S

AU - Ataseven, Beyhan

AU - Barlow, Ellen

AU - Beckmann, Matthias W

AU - Berger, Jessica

AU - Bisinotto, Christiani

AU - Bösmüller, Hans

AU - Boros, Jessica

AU - Brand, Alison H

AU - Brooks-Wilson, Angela

AU - Brucker, Sara Y

AU - Carney, Michael E

AU - Casablanca, Yovanni

AU - Cazorla-Jiménez, Alicia

AU - Cohen, Paul A

AU - Conrads, Thomas P

AU - Cook, Linda S

AU - Coulson, Penny

AU - Courtney-Brooks, Madeleine

AU - Cramer, Daniel W

AU - Crowe, Philip

AU - Cunningham, Julie M

AU - Cybulski, Cezary

AU - Darcy, Kathleen M

AU - El-Bahrawy, Mona A

AU - Elishaev, Esther

AU - Erber, Ramona

AU - Farrell, Rhonda

AU - Fereday, Sian

AU - Fischer, Anna

AU - García, María J

AU - Kruitwagen, Roy F P M

AU - van-Wagensveld, Lilian

AU - AOCS Group

AU - Ramus, Susan J.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

AB - BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

U2 - 10.1002/cncr.34582

DO - 10.1002/cncr.34582

M3 - Article

C2 - 36572991

SN - 0008-543X

VL - 129

SP - 697

EP - 713

JO - Cancer

JF - Cancer

IS - 5

ER -

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

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